N-Arylation of α-aminoesters with p-tolylboronic acid promoted by copper(II) acetate

Article abstract of DOI:10.1016/S0040-4039(02)02882-4

Copper-promoted N-arylation of α-amino esters with p-tolylboronic acid at room temperature was accomplished with little or no racemization.

Full text of DOI:10.1016/S0040-4039(02)02882-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1691–1694
N-Arylation of a-aminoesters with p-tolylboronic acid promoted
by copper(II) acetate
Patrick Y. S. Lam,* Damien Bonne, Guillaume Vincent, Charles G. Clark and Andrew P. Combs
Bristol-Myers Squibb Company, Experimental Station, PO Box 80500, Wilmington, DE 19880-0500, USA
Received 21 November 2002; revised 18 December 2002; accepted 19 December 2002
Abstract—Copper-promoted N-arylation of a-amino esters with p-tolylboronic acid at room temperature was accomplished with
little or no racemization. © 2003 Published by Elsevier Science Ltd.
Copper-promoted carbonꢀnitrogen (CꢀN) bond cross-
coupling reactions of NH-containing substrates with
arylboronic acids have emerged as a powerful synthetic
method since the initial reports by Chan and Lam.1
This novel methodology is characterized by the mild
reaction conditions (room temperature and weak base)
and is useful for the synthesis of nitrogen-containing
compounds in pharmaceuticals, crop-protection chemi-
cals and material sciences. Many extensions and appli-
cations of this new methodology have been reported.2–6
A series of aminoesters were arylated using p-tolyl-
boronic acid (Table 1) in 17–67% yield.12 The general
condition for this coupling reaction involves the addi-
tion of 2.0 equiv. of p-tolylboronic acid and 2.0 equiv.
of TEA (triethylamine was found to be a better base
than pyridine for amine substrate) to 1.0 equiv. of the
a-aminoester followed by 1.1 equiv. of anhydrous cop-
,
per(II) acetate and 4 A molecular sieves. The reaction
mixture is stirred open to air, protected from atmo-
spheric moisture, at room temperature for 1–2 days.
It is apparent from this study that the length of the
alkyl chain has an influence on the yield of these
cross-coupling reactions. In general, a-aminoesters with
small R groups (Table 1, entries 1 and 2) give poor
yields. We believe this is a consequence of the low
solubility of the corresponding a-aminoesters. In these
cases, the competing conversion of p-tolylboronic acid
to phenol followed by O-arylation is observed. For the
proline substrate (entry 15), the poor yield may pre-
sumably be due to the steric hindrance of the substrate.
a-Amino acids and their derivatives are important
chemical building blocks in organic and biological
chemistry. Reactions involving these building blocks
should be mild enough so as not to cause epimerization
of the chiral centers. Known methods of N-arylation of
amino acid derivatives are the coupling of a-amino
acids with aryl halides under elevated temperature
(improved Ullmann reaction)8,9 and the use of
triphenylbismuth diacetate.10 The drawback of the for-
mer reaction is substantial racemization, and for the
later it is the lack of commercially available arylbis-
muth reagents. We would like to report that general
N-arylation of enantiomerically pure a-amino esters
can be achieved with p-tolylboronic acid and copper(II)
acetate under mild conditions with little or no
racemization.
In each reaction we did not observe the formation of
the N,N-bisarylated product.4a This suggests that the
mono N-arylated product is less reactive than the pri-
mary amine under these conditions.
We also found that this reaction causes little or no
racemization13,14 (entries 2, 5, 6, 8, 11, 12, 13).
L
-Aspar-
* Corresponding author. E-mail: patrick.lam@bms.com
tic ester is the only substrate that has some racemiza-
0040-4039/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
PII: S0040-4039(02)02882-4

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P. Y. S. Lam et al. / Tetrahedron Letters 44 (2003) 1691–1694
Table 1. CꢀN bond cross coupling of p-methylphenylboronic acid and a-aminoesters
tion (entry 13, 93.8% ee) due to the extra activating
a-carbonyl group.
hypothesis which lead to their suggestion of using
molecular sieves to sequester water in order to increase
the yield. Reduction of biphenylboronic acid to
biphenyl was also observed as a side product.
In general, two equivalents of p-tolylboronic acid are
used for the copper-promoted N-arylation reactions to
achieve optimal yields. This is due to the competing
side reaction of the formation of p-cresol from p-tolyl-
boronic acid. We decided to investigate the cause of the
formation of the undesirable phenol which can serve as
a substrate that will undergo O-arylation. Biphenyl-
boronic acid was used in the absence of a NH-contain-
We hypothesized that the first step of the reaction
mechanism (Scheme 2) involves the rapid coordination
and dissolution of copper(II) acetate by the a-
aminoester to form the a-aminoester–copper(II) com-
plex A.15 The second step involves the transmetallation
of the p-tolylboronic acid with A to give the a-
aminoester-p-tolyl–copper(II) complex B. Complex B
may very slowly undergo reductive elimination to give
C. Alternatively, B can undergo air oxidation to yield
the corresponding higher oxidation-state copper(III)11
complex D which can now more efficiently reductively
18
ing substrate (Scheme 1). When O2 was used, no
isotope incorporation was observed. However, when
H2O18 was added to the reaction, O18 was incorporated
into biphenylphenol. Thus, the source of phenol forma-
tion is the O-arylation of water. This confirms Evans’1c

P. Y. S. Lam et al. / Tetrahedron Letters 44 (2003) 1691–1694
1693
Scheme 1. Phenol formation from biphenylboronic acid.
Scheme 2. Possible mechanism of N-arylation with p-tolylboronic acid.
eliminate to afford C. Quantitative analysis of an
analogous reaction mixture shows only trace amount of
copper(0) present at the end of the reaction. This
suggests that reduction elimination from a copper(II)
intermediate is not the major pathway.
Acknowledgements
We thank Dr. Paul S. Anderson, Dr. Carl P. Decicco
and Dr. Ruth R. Wexler for their support of this
research.
In summary, we have successfully N-arylated a-
aminoesters with little or no racemization using cop-
per(II) acetate and p-tolylboronic acid. This reaction
works under a very mild set of conditions: room tem-
perature, mild base (triethylamine) and in the presence
of air. We continue to explore the mechanism and
scope of this powerful copper-promoted C-heteroatom
cross-coupling reaction with organometalloids.
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,
(90.5 mg, 0.667 mmol, 2.0 equiv.), 4 A molecular sieves
(250 mg), 3 mL of dry dichloromethane, triethylamine (93
mL, 0667 mmol, 2.0 equiv.), L-phenylalanine methyl ester
hydrochloride (71.5 mg, 0.333 mmol, 1.0 equiv.) and
cupric acetate (66.7 mg, 0.367 mmol, 1.1 equiv.). The
progress of the reaction was monitored by TLC (eluent:
15% ethyl acetate/hexane). After 15 min, 80% of the
starting material was consumed. The reaction was
allowed to stir under air at room temperature for 24 h.
The reaction was quenched by a solution of 3 mL of 2 M
NH3 in methanol. The solvent was evaporated under
reduced pressure and the residue dissolved in 3 mL of
dichloromethane and purified by silica gel chromatogra-
phy (eluent: 15% ethyl acetate/hexane) to give 57.8 mg of
N-p-tolylphenylalanine methyl ester (75% yield) as a
1
colorless solid. H NMR (300 MHz, CDCl3): l 7.32–7.21
(m, 5H), 6.98 (d, J=8.2 Hz, 2H), 6.52 (d, J=8.2 Hz, 2H),
4.36 (t, J=6.1 Hz, 1H), 3.68 (s, 3H), 3.12 (t, J=5.9 Hz,
2H), 2.22 (s, 3H); MS AP+: 270.5 [M+H]+ (70%), 539.3
[2M+H]+; HRMS calculated for C17H20NO2 [M+H]+ m/
z=270.1494, found m/z 270.1484. Anal. calcd for
C17H19NO2, 0.17H2O, C, 74.96; H, 7.16; N, 5.14; found:
C, 74.96; H, 7.03; N, 5.14%.
13. Chiral reverse-phase HPLC provided baseline resolution
of the enantiomers from which any racemization could be
determined.
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amides.
15. Cupric acetate is insoluble in CH2Cl2 (colorless solution),
the preferred solvent. When the amine substrate is added
an instantaneous deep blue color results, suggesting the
coordination and dissolution of Cu(OAc)2 as the first step
of the reaction.
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